PEER REVIEWED

Intra-arterial Chemotherapy for Retinoblastoma

A promising treatment modality, with eyes and lives being saved.

S. K. Steven Houston, III, MD • Timothy G. Murray, MD, MBA • Cristina E. Fernandes, MD • Mohammad A. Aziz-Sultan, MD

Retinoblastoma treatment continues to evolve, with primary management focusing on focal treatments for early disease and systemic chemotherapy combined with focal consolidation for most other tumors.

External beam radiation therapy (EBRT) has been less commonly used over the past decade, and enucleation is reserved for advanced disease and those tumors that fail other treatment modalities. With the advances in treatment modalities and timely diagnosis, survival rates have climbed to 95% in specialized centers, with the majority of children maintaining useful vision.

Despite the success in treating retinoblastoma tumors, current treatments are not without risks. Three-drug chemotherapy, with vincristine, etoposide and carboplatin, presents toxic pharmaceuticals to infants and young children—with the risk of pancytopenias and potential hospitalizations, antibiotic therapy and transfusions. Systemic carboplatin has also been shown to affect hearing development, with reports of 5%¹ and higher, for a cumulative incidence of approximately 12%. Finally, advanced retinoblastoma tumors that continue to have tumor activity despite treatment require enucleation, with studies showing that 47% to 83% of advanced tumors—defined as International Classification of Retinoblastoma (ICRB) group D or Reese-Ellsworth (R-E) stage Vb—can be controlled with current treatment protocols.^2,3

At Bascom Palmer Eye Institute (BPEI), tumor control rates for R-E stage I-IV tumors are 100%, with stage Vb tumor control rates approaching 85%. Recent developments in retinoblastoma treatment have focused on the use of superselective intra-arterial chemotherapy, both as salvage treatment and primary management. The current article will discuss early experiences with this exciting new technique.

Figure 1. Left eye of a child with large macular retinoblastoma before treatment (top) and after intra-arterial melphalan and focal laser consolidation (bottom).

THE RESEARCH SO FAR

Intra-arterial chemotherapy for retinoblastoma was first investigated by Reese et al. in 1955,⁴ and they reported on the success of intracarotid triethylene melamine combined with radiotherapy. In 1993, almost 40 years later, this delivery technique was revisited by a group in Japan, as they pioneered the use of selective administration of chemotherapy to the ophthalmic vasculature to deliver localized treatment to retinoblastoma tumors.^5,6

In 2004, Reese et al. reported on the use of a ballooned catheter that was advanced beyond the ostium of the ophthalmic artery. In their technique, blood flow was occluded distally, followed by infusion to deliver chemotherapy selectively to the eye without reflux and exposure to the brain. They reported a 97% technical success rate in 610 eyes of 187 patients (563 treatments). Although the authors did not report on the success of the treatment, they noted that there were no significant adverse events, including cerebral ischemia, and complications were minimal, with transient bradycardia, periorbital erythema and swelling.

In order to prevent the need to occlude distal flow with the subsequent risk of ischemic events, more selective techniques were developed to cannulate selectively the ophthalmic artery directly. Although the use of this technique in the treatment of retinoblastoma is fairly new, several groups have reported on their early experiences, with impressive results as both primary and salvage treatments, often salvaging advanced eyes destined for enucleation.

In 2008, Abramson et al.⁷ reported their initial findings in a phase 1/2 study on the use of superselective intra-arterial chemotherapy for retinoblastoma. After demonstrating that seven of nine children with advanced tumors (R-E stage V) could be spared enucleation with this new technique and without severe adverse effects, they paved the way for other investigations into this novel treatment.

Following this initial report on the use for salvage treatment, Abramson et al.⁸ published their three-year experience with this technique on 28 eyes (75 infusions) of 23 children newly diagnosed with retinoblastoma. Eighty-nine percent (25 of 28 eyes) were R-E stage V, with only 3.5% (one of 28 eyes) requiring enucleation secondary to tumor progression and 0% requiring adjuvant systemic chemotherapy or radiation. Cannulization was successful in 100%, with patients requiring a mean of 3.2 infusions of melphalan only (12 of 28, 43%) or melphalan combined with other agents (topotecan, carboplatin). Estimates of globe-salvage were shown to be 100% at one year and 89% at two years (95% CI, 43%-98%). There were no serious adverse effects of stroke, death or hemorrhage, and ophthalmic complications were minimal, including lid edema, forehead hyperemia and eyelash loss. There were several episodes of neutropenia, with zero requiring hospitalization.

Figure 2. Left eye (left images) and right eye (right images) of a child with bilateral retinoblastoma before treatment (top images) and after bilateral intra-arterial melphalan and laser consolidation (bottom images).

For patients with bilateral disease, Abramson et al.⁹ also reported on the use of tandem therapy, or bilateral infusions, during the same session. In a report of four patients with advanced bilateral retinoblastoma (R-E stage V), all eyes avoided enucleation or radiation, without any serious adverse effects.

More recently, Gobin et al.¹⁰ reported on the four-year experience with intra-arterial chemotherapy for retinoblastoma on 95 eyes (259 infusions) of 78 patients. Of these, 54.7% were salvage treatment, having failed prior treatment with chemoreduction or EBRT. Successful cannulation occurred in 98.5% of patients, with a mean of 3.1 infusions per eye. With a median follow-up of 13 months, eyes with disease severity below R-E stage V did not require enucleation or irradiation. However, in those with advanced disease (R-E stage V), 22.9% (19 of 83) required enucleation for persistent tumor activity, notably vitreous seeding. Estimates of ocular event-free survival were 70% of all eyes, 81.7% for eyes treated with intra-arterial chemotherapy as primary management, and 58.4% for eyes that failed primary treatments with chemoreduction or EBRT. Complications included periocular inflammation (10.5%), madarosis (12.6%), and avascular retinopathy with complete vision loss in four patients (4.2%), as well as neutropenia (11.4%).

At BPEI, Mutapcic et al.¹¹ reported on the initial experience with supraselective intra-arterial infusion of melphalan as salvage therapy in 12 eyes of 10 children. All patients had advanced tumors (R-E class Vb or ICRB Group D) previously treated with systemic chemotherapy and laser consolidation, but these eyes had continued tumor activity and were destined for enucleation. Cannulation rates were 100%. Initial responses demonstrated tumor regression, including vitreous and subretinal seeds. At six-month follow-up, 75% (nine of 12 eyes) had continued tumor control; however, 25% (three of 12 eyes) showed tumor progression and were enucleated.

Mutapcic et al.¹² reported on the histopathologic findings accompanying the enucleated eyes, with 67% (two of three) exhibiting evidence of viable tumor with high-risk characteristics, including vitreous seeding in all eyes, choroidal invasion in one eye, and two of three with invasion of the optic nerve to the lamina cribrosa or just anteriorly. Side effects included neutropenia, as well as several unique complications not previously reported, including intraretinal hemorrhages, peripapillary cotton wool spots that resembled Purtscher's-like retinopathy, vitreous hemorrhages and myositis. Besides neutropenia, these complications were thought to be related to the treatment technique, rather than the chemotherapy drug used or the dosage.

Also at BPEI, Peterson et al.¹³ reported on further series with the treatment of 17 tumors in 15 patients (26 infusions). Mean follow-up was 8.6 months, with 76.5% exhibiting tumor control and avoiding enucleation. Of those that showed tumor control, 54% showed a response after a single infusion.

Interestingly, those patients treated with a lower initial dose (3 or 5 mg of melphalan), had a higher rate of enucleation (36%) compared to those that received a higher initial dose (7.5 mg), even though those at the lower dosages received retreatment with a high dose (7.5 mg). In addition, of those treated at lower initial dosages and retreated at higher dosages, four eyes had delayed vitreous hemorrhages, whereas these complications were not seen in those treated with initial high dosages.

Figure 3. Superselective ophthalmic artery cannulation, followed by an angiogram showing vascular supply to the eye and focal delivery of chemotherapy.

Further consideration is also needed pertaining to the vasculature in patients previously treated with systemic or local chemotherapy, as well as radiation. BPEI has reported on the vascular alterations of these treatment modalities, which may potentially decrease the delivery of chemotherapeutics during intra-arterial infusion.¹⁴

Finally, Shields et al.¹⁵ reported on their initial experiences with superselective intra-arterial chemotherapy for retinoblastoma tumors that had failed chemoreduction or in children whose parents wanted to avoid systemic chemotherapy or enucleation. In 11 cases treated with three sessions of melphalan at 5 mg, initial responses demonstrated tumor regression. However, on follow-up, 27% (three of 11) had recurrent or persistent vitreous seeding, and one case had a vitreous hemorrhage. Side effects included minor complications, such as eyelid edema and ptosis, as well as moderate cytopenias. At this time, a full presentation of their results are not available, with publication pending.

LOOKING FORWARD

Although the previous groups have reported the incidence of several concerning complications, including avascular retinopathy with visual loss, ischemic retinal changes, and vitreous hemorrhages, Munier et al. reported on vascular complications in their cohort of 13 patients. With a mean follow-up of seven months, 92.3% had tumor regression, while one patient (7.7%) required external beam radiation.

Of concern, two eyes (15.4%) sustained sectoral choroidal occlusive vasculopathy resulting in areas of chorioretinal atrophy. The etiology of these vascular complications remains unknown but did not appear to be melphalan-dose dependent. Subsequent injections resulted in the extension of the atrophy into the macula in one patient. As seen in other initial studies, one patient developed a delayed vitreous hemorrhage. Finally, one patient with a technically difficult cannulation suffered emboli to the retina, manifesting as multiple Roth spots in the posterior pole.

With any new treatment or technique, these initial experiences serve as a guide in modifying treatment protocols. Superselective intra-arterial chemotherapy for retinoblastoma remains in its early stages of development, with many questions still remaining. Current reports lack sufficient follow-up on long-term efficacy, safety and side effect profiles. However, to date, there have not been any deaths or strokes in any of the children treated with intra-arterial chemotherapy.

Side effects appear to be related to the treatment technique, with several vision-threatening side effects being reported. Additionally, treatment protocols vary by institution, resulting in drug questions, including the use of one chemotherapeutic such as melphalan or the primary use of another agent or a combination approach. Finally, optimal dosing of chemotherapeutics remains to be determined.

CONCLUSION

Intra-arterial chemotherapy delivers targeted, high-dose chemotherapy to the eyes of children with retinoblastoma. Preliminary studies have demonstrated the effectiveness of this novel therapy both as salvage and primary management. No deaths or strokes have been observed, but vision-threatening vascular complications have been reported.

Much remains to be determined regarding the long-term efficacy and safety, candidate chemotherapeutics, and optimal dosing and treatment protocols. The data from the above groups as well as others have been pivotal in establishing the use of intra-arterial chemotherapy in children with retinoblastoma and developing the framework for a proposed multi-centered collaboration initiated by the Childrens' Oncology Group. We anticipate this clinical trial, as well as continued reports with long-term follow-up, to define further the use of this treatment in the current armamentarium to save the lives and vision of children with this disease. RP

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